The High-Dose Aldesleukin “Select” Trial: A Trial to Prospectively Validate Predictive Models of Response Treatment in Patients With Metastatic Melanoma

High-dose aldesleukin (HD-IL2) produces durable responses in a portion of patients with melanoma. In the modern era, HD-IL2 is a key component of tumor infiltrating lymphocyte (TIL) therapy and newer forms of IL-2 have shown promise across tumor types. The Select trial aimed to validate biomarkers of HD-IL2 responsiveness. First, we retrospectively identified a proinflammatory (Class 2) gene expression profile (GEP) associated with HD-IL2 responsiveness. Prospective biomarker discovery was then performed in patients with metastatic melanoma receiving HD-IL2 with a primary objective to validate Class 2 GEP as a predictor of efficacy. Additional analyses examined potential serum and tissue protein biomarkers. Retrospective GEP data (n=28) demonstrated a response benefit in GEP Class 2 versus Class 1 subgroup (ORR: 86% vs. 38%; P =0.0384). In the prospective cohort with GEP data (n=152), HD-IL2 resulted in an ORR of 17.7%, a median PFS of 2.4 months (95% CI: 2.1–2.8 mo) and median OS of 21.2 months (95% CI: 19.0–25.5 mo). Using gene set enrichment analysis, Class 2 GEP tumors had a higher response (21% vs. 12%; P =0.2678) and 2-year OS (37.2% vs. 22.4% P =0.1229) in comparison to Class 1 but did not meet predefined levels of significance. Serum proteomic analysis highlighted that low C-reactive protein was associated with response. In conclusion, although Class 2 GEP did not meet the predefined measure of significance, it correlated with response and lower CRP levels were associated with improved outcomes. Building on this work, future biomarker studies are primed to guide contemporary IL-2 administration